Examination of the D₂/5-HT₂ Affinity Ratios of Resolved 5,6,7,8,9,10-Hexahydro-7,10-iminocyclohept[b]indoles: An Enantioselective Approach toward the Design of Potential Atypical Antipsychotics

Enantiomers of several N-substituted 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[6]indoles were obtained by the resolution of 2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole and 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole followed by N-alkylation. These, as well as the racemates, were evaluated for their affinity for the 5-HT₂ and D₂ receptors. Those compounds possessing the 7S,10R stereochemistry were consistently recognized by the 5-HT₂ and D₂ receptors as the eutomer. 2-Fluoro-11-[4-(4-fluorophenyl)-4-oxobutyl]-5,6,7,8,9,10-hexahydro-7S,10R-iminocyclohept[b]indole [(7S,10R)-8] had the highest affinity for the 5-HT₂ receptor (K_i = 0.80 nM), while its distomer (7R,10S)-8 was the most selective member of this class of bridged γ-carbolines (D₂/5-HT₂ = 562). Incorporation of a benzoyl or isosteric benzisoxazole moiety tethered by a four-carbon spacer to a bridged γ-carboline nucleus, possessing the 7S,10R absolute configuration, produced high affinity ligands for the 5-HT₂ and D₂ receptors.